Available at: http://rjpharmacognosy.ir Copy right© 2014 by the Iranian Society of Pharmacognosy

*Corresponding author: s.fahimi@sbmu.ac.ir, Tel/Fax: +98 21-88776027

Research Journal of Pharmacognosy (RJP) 4(4), 2017: 71-85

Received: 14 Dec 2016

Accepted: 24 June 2017

Review article

Plants used to treat hyperpigmentation in Iranian traditional medicine: a

review

S. Ghafari1, Sh. Fahimi

2*, Sh. Sahranavard

2

1Traditional Medicine and Materia Medica Research Center (TMRC), Shahid Beheshti University of Medical

Sciences, Tehran, Iran.

2Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical

Sciences, Tehran, Iran.

Abstract Skin hyperpigmentation is characterized as increased production and accumulation of melanin, which

could be aesthetically unfavorable and develops serious skin diseases. There is a need to find new

depigmenting agents, since many current natural and synthetic products present undesired side effects.

In Iranian traditional medicine (ITM), plants have been used for the treatment of skin diseases such as

hyperpigmentation. In this study, topical herbal medicines, for the treatment of hyperpigmentation

were searched in ITM references, and their scientific names were identified, using different

comprehensive glossaries. Thereafter, depigmenting mechanisms of these genera were reviewed in

recent scientific literatures. Seventy-nine plants were made known as herbal remedies for skin

hyperpigmentation. Furthermore, modern literatures have shown depigmenting effect of about 40% of

these plants or their isolated compounds, with different melanogenesis inhibitory mechanisms with

tyrosinase inhibition as the most revealed method. Regarding the new approach to medicinal plants in

recent years, a large number of medicinal herbs that were mentioned in ITM references would be good

candidates for exploring new herbal medicines for skin hyperpigmentation disorders.

Keywords: herbal medicine, hyperpigmentation, Iranian traditional medicine

Introduction

Skin pigmentation is a broad term, usually

reflecting an increased and dispersion of melanin,

the pigment that gives human skin, hair, and eyes

their color [1,2]. Epidermal and dermal

hyperpigmentation can be dependent to either

increased numbers of melanocytes or activity of

melanogenic enzymes [3]. Hyperpigmentary

problems such as post inflammatory,

hyperpigmentation, solar lentigo, and melasma,

occur widely in the human population, and are

considered to be skin disorders and cause

psychological disturbances [4].

Since skin hyperpigmentation is related to the

chemical nature of melanin, tyrosinase activity,

tyrosinase-related protein-1 (TRP-1) and

tyrosinase-related protein-2 (TRP-2) in the

melanocytes, and the transfer of melanin in the

keratinocytes, several treatment methods such as

Ghafari S. et al.

72 RJP 4(4), 2017: 71-85

inhibition or attenuation of tyrosinase and related

melanogenic enzymes catalytic activity,

transcriptional regulation and post-translational

modification of melanogenic enzymes,

interruption of melanosome transfer, acceleration

of epidermal turnover have been investigated

[2,5].

Tyrosinase is the key enzyme of melanogenesis

and the first in the conversion of tyrosine to

melanin. It is a common target for therapeutic

agents intended to alleviate cutaneous

hyperpigmentation. By using purified mushroom

tyrosinase or cell lysates of melanoma cells

tyrosinase inhibitory effect could be determined

[2]. Mushroom tyrosinase, the enzyme extracted

from the champignon mushroom Agaricus

bisporus, is highly homologous and

commercially available, thus making it well

suited as a model for studies on melanogenesis,

and has been used by many studies carried out on

tyrosinase inhibition [2,5].

Hydroquinone and its derivations, such as

arbutin, and kojic acid are some of the common

and effective whitening agents to treat

hyperpigmentation disorders with mechanism of

inhibition of tyrosinase [6,7]. In spite of their

efficacy, the mentioned whitening agents would

cause some adverse effects such as sensitization,

contact dermatitis and erythema and also

cytotoxic and mutagenic effect with prolonged

exposures [4,8].

The long-term use of herbs, introduced in

traditional medicines, confirms their value in

drug discovery [9]. Surprisingly, many crude

drug and plant extracts have been reported to

inhibit the tyrosinase enzyme [4]. The “return to

nature” trend of recent years had been

accompanied by a thriving interest in whitening

agents from herbal medicine [10] with most of

the population still believing in traditionally

crude drugs and medicinal plants to treat

hyperpigmentation [4].

Iranian traditional medicine (ITM), which dates

back to over 6000 years [11], was a combination

of different medical traditions from Greece,

Egypt, India and China. Iranian physicians such

as Rhazes and Avicenna were merging all

existing information on medicine at that time,

and have also theorized their own examination

and wise perception [12].

In ITM references, the most used terms

denoting skin hyperpigmentation are ‘Kalaf’,

‘Bahaq’ and ‘Namash’ [13-16]. Review of

Iranian Traditional Medicinal books showed that

‘Kalaf’ was a kind of skin darkness or brown to

black pigmentation that usually occurred on the

face with clinical manifestations similar to

melasma [17,18]. ITM scholars believed that

‘Bahaq’ was similar to ‘Kalaf’ except that

‘Bahaq’ was associated with sloughing and

roughness [15]. According to humoral theory in

ITM, abnormal black bile congestion in skin

layers and its increased concentration caused

dark color spots on the face, known as “Namash”

being equivalent to freckles [19].

There are many medicinal plants, which have

been utilized for the treatment of

hyperpigmentation by Iranian physicians, which

are yet to be fully verified experimentally.

In this study, the medicinal plants used for the

treatment of hyperpigmentation in ITM

references via topical route of administration

were reviewed. Subsequently, melanogenesis

inhibitory effects of these species were searched

in recent scientific literatures.

Methods

Traditional search

Three famous books including Liber continens,

the Canon of medicine and Makhzan-ul-adviah

were selected as the main references of ITM.

Liber continens (al-Hawi fi al-tibb)

Abu Bakr Muhammad ibn Zakariya Razi

(Rhazes), a renowned Iranian physician, chemist

and philosopher (865–940 A.D.) wrote the book

of al-Hawi fi al-Tibb. This book is the most

important book of Rhazes, and was repeatedly

printed in Europe during the 15th and 16

th

centuries, under the title ‘Liber Continens’. It had

a major influence on the development of medical

practices in Europe. Rhazes surveyed Greek and

Plants for treatment of hyperpigmentation in ITM

73

early Arabic medicine, as well as various Indian

medical knowledge. Furthermore, during his

work, he added his own considered judgment and

medical experience as commentary [9].

The Canon of medicine

The Canon of medicine is the best work on

traditional medicine, which was compiled by Abu

Ali Al- Hussain ibn-e Abdullah- ibn-e- Sina,

known as Avicenna, one of the most famous

Iranian physician (980-1037 A.D.). The Canon of

medicine was used in over half a century in

European scientific centers as a medical

textbook, and was later translated into different

languages [20]. It consists of five books, and

serves as a concise reference in traditional

medicine. The second book contains an estimate

of 800 individual drugs, mostly of medicinal

plants (and some animal and mineral substances).

Avicenna added his own comments, highlighting

the differences between recipes from different

sources, and occasionally, there were some

disagreement regarding them. Thus, he gave his

opinion of the effectiveness (or ineffectiveness)

of some remedies [21].

Makhzan-ul-adviah Makhzan-ul-adviah written by Aghili Alavi Khorasani, one of the prominent Persian physicians (1772 A.D.), is a significant reference about traditional medicine and medical terminology in Persian. About 1744 individual drugs of plant, mineral and animal origin used in traditional medicines, have been described in Makhzan-ul-adviah. It is a collection of his lifetime medical notes, summarized from everything he had read, as well as observations from his own medical experiences [22]. Plants to treat hyperpigmentation in ITM references ITM references were searched in order to find a list of traditional names of medicinal plants, used for the treatment of hyperpigmentation, via topical route of administration with the main keywords: ‘Bahaq’, ‘Kalaf’ and ‘Namash’.

Thereafter, plants were identified by different comprehensive glossaries by matching their traditional names with scientific names [23,24]. Modern search Plants with melanogenesis inhibitory effect in modern scientific databases In order to find melanogenesis inhibitory effect of the plants, a substantial search of scientific databases such as ‘Google Scholar’, ‘Scopus’ and ‘PubMed’ was carried out, using the genera in combination with key terms such as ‘hyperpigmentation’, ‘melanogenesis’ and ‘tyrosinase’.

Results and Discussion

Based on the ITM references, about 71 traditional names of medicinal plants, applied to treat skin hyperpigmentation (‘Bahaq’, ‘Kalaf’and

‘Namash’) via topical route of administration were found. The plants have been listed based on their scientific names. Moreover, their repetition in the Canon of medicine, Liber continens and Makhzan-ul-adviah along with the traditional names of the plants, phonetic spellings, families

and used organs have been shown (table 1). In modern literatures, all of the plants mentioned in table 1 were searched for hyperpigmentation inhibitory effect, and the mechanisms of interference with melanin synthesis according to their genera. The results are as follows:

Tyrosinase inhibition Quercetin-3'-O-β-D-glucoside was isolated from Allium cepa and inhibited melanogenesis without cytotoxicity. It inhibited melanin formation in B16 melanoma cells and mushroom tyrosinase

[25]. In a study, among 67 tropical plants evaluated for anti-tyrosinase activity, Althaea officinalis demonstrated moderate mushroom tyrosinase inhibitory effect [26]. Aristolochia bottae Jaub.& Spach and

magnoflorine, a compound isolated from A. debilis, had tyrosinase inhibitory activity via colorimetric method [27,28].

Ghafari S. et al.

74 RJP 4(4), 2017: 71-85

Table 1. Plants used for the treatment of hyperpigmentation via topical route of administration in ITM references; The Canon of

medicine (C), Liber continens (L), Makhzan-ul-adviah (M)]

Scientific name Family Traditional

name

Phonetic

spelling

Used

Parts kalaf bahaq namash

Achillea ptarmica L. Asteraceae Oodo-ul-otas /uːdɔːlɔːtæs/ Root - M -

Alcea digitata Alef.

Althaea officinalis L. Malvaceae Khatmi /χætmɪ/ Seed - LCM -

Alkanna tinctoria (L.) Tausch Boraginaceae Abukhalsa /æbuːχælsɑː/ Leaves,

root - LCM -

Allium sp. Alliaceae Korath /kɔːrɑːθ/ Seed,

root C - -

Allium cepa L. Alliaceae Basal /bæsæl/ Seed M CM -

Alyssum sp. Brassicaceae Alooson /æluːsɔːn/ - LCM - -

Amygdalus communis L.

(Prunus amygdalus L.) Rosaceae Louz /ləʊz/

Seed,

root, oil L - L

Apium graveolens L. Apiaceae Karafs /kæræfs/ Leaves, branches

- - L

Aristolochia sp. Aristolochiaceae Zaravand-e-Modahraj

/zærɑːvændemɔː

dæhrædʒ/ Root CM - -

Arum italicum Mill. Araceae Loof /luːf/ Root CM CM C

Astragalus sp. Fabaceae Katira /kætiːrɒː/ Gum M M M

Beta vulgaris L. Chenopodiaceae Selgh /selɢ/ Leaves CM M CM

Brassica nigra (L.) K.Koch Brassicaceae Khardal /xærdæl/ - LCM C

Brassica oleracea L. Brassicaceae Karnab /kærnæb/ Seed,

leaves ML L ML

Bryonia sp. Cucurbitaceae Fashara /fɑːʃærɑː/ Root CM - -

Caesalpinia bonduc (L.)Roxb Caesalpiniaceae Rateh /ræte/ - C - -

Capparis sp. Capparaceae Kabar /kæbær/ Fruit - ML -

Carthamus tinctorius L. Asteraceae Ehriz /əhrɪz/ Fruit C CM M

Cicer arietinum L. Leguminosae Hemmas /hemmæs/ - CM L CM

Citrus medica L. Rutaceae Otroj /əʊtrəʊdʒ/ Fruit CM - -

Convolvulus scammonia L. Convolvulaceae Saghmoonia /sæɢmu:nɪɒː/ Sap CM CM M

Costus sp. Costaceae Quost /ɢoʊst/ Root CM - -

Cucumis colocynthis L. Cucurbita mexicana Dammann

Cucurbitaceae Qar /ɢær/ The

rind - M -

Cucumis melo L. Cucurbitaceae Bettikh /bettɪχ/ Seed, Peel

CM CM -

Cucumis sativus L. Cucurbitaceae Qessa /ɢessæ/ Fruit - L -

Curcuma zedoaria (Christm.)R

oscoe Zingiberaceae Jadvar /dʒædvɑːr/ Root M M -

Daphne mezereum L. Thymelaeaceae Mazarioon /mɒzærɪʊn/ Leaves L L -

Dorema sp. Apiaceae Oshagh /ɔːʃæɢ/ Gum M M -

Ecballium elaterium (L.) A.

Rich. Cucurbitaceae Qesa-ul-hemar

/ɢesɑːəʊlhəmɑːr

/ Fruit M M -

Eruca sativa Mill. Brassicaceae Jerjir /dʒerdʒɪr/ Seed CM M CM

Ficus carica L. Moraceae Teen /ti:n/ - M LCM -

Plants for treatment of hyperpigmentation in ITM

75

Scientific name Family Traditional

name

Phonetic

spelling

Used

Parts kalaf bahaq namash

Flemingia grahamiana Wight

&Arn.

Acanthaceae

Varas

/væræs/

Fruit

CM

M

CM

Gentiana lutea L. Gentianaceae Gentiana /dʒentɪɑːnɑː/ Root - CM -

Gypsophila struthium Loefl. Caryophyllaceae Kondosh /kɔːndɔːʃ/ Root CM CM -

Hemerocallis sp. Hemerocallidaceae Sousan /su:sæn/ Root CM M -

Hypericum sp. Clusiaceae Houfariqun /hu:fɑ:rɪɢu:n/

Flower,

arial parts

M M -

Hyssopus officinalis L.

Nepeta sp. Lamiaceae

Zoofa-ye-

yabes /zu:fɑːjejæbes/

Arial

parts CM - -

Indigofera tinctoria Mill. Chrozophora tinctoria (L.)

A.Juss.

Fabaceae Nil /niːl/ - CM CM -

Iris sp. Iridaceae Irsa /iːrsɒː/ Seed, root

CM M CM

Jasminum sp. Oleaceae Yasmin / jæsmɪn/ Leaves,

fruit CL -

Laurus nobilis L. Lauraceae Qar /ɢɒːr/ - M CM -

Lepidium draba L.

Plumbago europaea L.

Brassicaceae

Plumbaginaceae Qonabari /ɢɔːnɒːbærɪ/

Arial

part CM CM -

Lepidium sativum L. Brassicaceae Horf /hɔːrf/ Seed M M M

Linum sp. Linaceae Katan /kætɑːn/ Seed C - -

Lolium temulentum L. Poaceae Shailam /ʃæjlæm/ Seed - CM -

Lupinus termis L. Fabaceae Tormes /tɔːrmes/ Seed CM LCM -

Lycium afrum L. Brassicaceae Hozoz /hɔːzɔːz/ Leaves,

seed LC - -

Mandragora officinarum L. Solanaceae Yabrooh- os-

sanam /jæbruːhɔːssænæm/ Sap CM - CM

Moringa arborea Verdc. M. oleifera Lam.

Moringaceae Ban /bɒːn/ Seed LC LC LC

Muscari comosum (L.) Mill. Hyacinthaceae Balboos /bælbu:s/ Bulb CM M

Myrtus communis L. Myrtaceae Ass /ɒːs/ Leaves CM LC CM

Narcissus sp. Amaryllidaceae Narjes /nærdʒes/ Flower,

seed CM CM -

Nerium sp. Apocynaceae Defli /deflɪ/ Leaves - M -

Nymphaea sp. Nymphaeaceae Niloofar /nɪluːfær/ Root - L -

Persicaria hydropiper (L.)

Delarbre Polygonaceae

Zanjabil-ul-

kelab

/zændʒæb

iːləʊlkelɑːb/

Arial

parts CM - -

Pistacia sp. Anacardiaceae Habbat-ul-

khazra /hæbbætəʊlχæzræ/ Fruit CM - -

Polygonum hydropiper L. Polygonaceae Felfel-ul -ma /felfelɔːlmɒː/ Fruit L - L

Portulaca oleracea L. Portulacaceae Khorfah /χɔːrfæ/ Leaves - - M

Raphanus sp. Brassicaceae Fojl /fəʊdʒl/ Seed,

leaves - CM -

Rheum sp. Polygonaceae Ravand /rɒːvænd/ Root LCM - -

Ricinus communis L. Euphorbiaceae Karchak /kærtʃæk/ Seed CM - -

Table 1. Continued

Ghafari S. et al.

76 RJP 4(4), 2017: 71-85

Scientific name Family Traditional

name

Phonetic

spelling

Used

Parts kalaf bahaq namash

Rosa canina L. Rosa moschata Herrm.

Rosaceae

Nasrin

/næsrɪn/

Flower

M

-

-

Rubia tinctorum L.

R. cordifolia L Rubiaceae Fovvah /fɔːvvæh/ Root - M -

Ruta graveolens L. Rutaceae Sodab /səʊdɒːb/ Leaves C CM -

Senna sp. Caesalpiniaceae Sena-e-makki /senɑːmækkɪ/ Leaves M M -

Trachyspermum copticum (L.) Link Apiaceae Nankhah /nænχɒːh/ Seed CM CM

Trigonella foenum-graecum L. Fabaceae Holbah /həʊlbæ/ Seed LCM - -

Triticum vulgare Vill. Poaceae Hentah /hentæ/ Seed CM - -

Urginea maritima (L.) Baker Hyacinthaceae Eshghil /eʃɢiːl/ Root - - M

Vicia faba L. Fabaceae Baghela /bɒːɢelɒː/ Bark,

fruit LCM LC LCM

Vicia ervilia (L.)Willd. Fabaceae Karasnah /kæræsnæ/ Seed CM C C

-: not mentioned

Choi et al. investigated the effects of whitening,

anti-wrinkling and safety of acetone extract of

Astragalus sinicus Linne seeds and reported that

it may be useful as a potential agent for

functional cosmetic products [29]. Hee Kim et al.

suggested that calycosin isolated from A.

membranaceus (Fisch.) Bunge might be an

effective skin-lightening agent. According to the

studies, calycosin demonstrated tyrosinase

inhibitory activity with melanin biosynthesis

inhibition zone in a culture plate of Streptomyces.

Moreover, it dramatically reduced melanin

synthesis of Melan-a cells, without any apparent

cytotoxicity, and reduced expression of

tyrosinase [30].

The inhibitory effect of brazilein (a compound

isolated from the methanol extract of

Caesalpinia sappan) on tyrosinase activity was

evaluated using multi-spectroscopic and

molecular docking techniques. The results

showed a dose dependent inhibitory effect of

brazilein against tyrosinase activity, which was

significant to kojic acid as the positive control. In

addition, the inhibitory effect of brazilein on

cellular tyrosinase and melanin synthesis in B16

cells was found to be in a dose dependent manner

[31].

The active principle compounds isolated from the

seeds of Carthamus tinctorius demonstrated a

significant inhibition for mushroom tyrosinase. It

was also found that N-feruloylserotonin and N-

(p-coumaroyl) serotonin strongly inhibited the

melanin production of Streptomyces bikiniensis

and B16 melanoma cells, in comparison with a

known melanogenesis inhibitor, arbutin [32].

Adhikari et al. have stated that fresh peel of

Citrus aurantifolia (Christm.) Swingle and C.

aurantium L. exhibited mushroom tyrosinase

inhibitory activity [4]. In another study, C.

sinensis (L.) Osbeck showed tyrosinase

inhibitory activity alone, and in combination with

other extracts such as Capparis spinosa, Olea

europaea and Oryza sativa, evaluated by in vitro

and in vivo models. The skin whitening effect and

the skin tolerance of this combination in

comparison with kojic acid and hydroquinone,

demonstrated more extensive effect [33]. Wu et

al. evaluated the whitening properties of six

different varieties of Taiwanese pummel (C.

grandis Osbeck). One of the varieties, known as

Touyu inhibited tyrosinase, which was almost

similar to the inhibition shown by kojic acid.

They claimed that C. grandis had high potential

for using as ingredients in products that prevent

skin pigmentation [34]. Several researchers have

reported the tyrosinase inhibitory effect of some

Table 1. Continued

Plants for treatment of hyperpigmentation in ITM

77

by-products, flavonoids and essential oils

extracted from citrus family. Based on the results,

citrus hydrosols demonstrated better inhibitory

effect than L-ascorbic acid, a well-known

tyrosinase inhibitor compound [35]. It has been

revealed that nobiletin, a polymethoxy-flavonoid

occurring exclusively in citrus fruits, appeared to

be more powerful than kojic acid in reduction of

tyrosinase activity [36]. In another study, C.

sinensis flavonoid fraction from fruits showed

about 60% tyrosinase inhibition [37]. The

essential oils, extracted from fruit peels of C.

grandis and C. hystrix DC, showed IC50

comparable to the kojic acid as the positive

control [38].

In a research, Baurin et al. have screened anti-

tyrosinase activity of sixty-seven tropical plants.

According to the results, Costus spicatus exhibited moderate tyrosinase inhibitory activity

[26].

A topical cream containing 4% concentrated

extract of Ficus carica fruit (w/o emulsion),

significantly reduced the skin melanin, trans-

epidermal water loss and skin sebum, and

increased the skin hydration. It also showed

insignificant effects on skin erythema and sebum

content and could possibly be used against

hyperpigmentation, acne, freckles and wrinkle

[39]. Nerya et al. realized that 3-(2,4-

dihydroxyphenyl propionic acid), DPP acid,

isolated from the leaves of F. carica, might

increase shelf life of intact mushrooms by

treatment with H2O2, followed by DPP acid or for

cut mushrooms by licorice extract or DPP acid

alone [40].

Curto et al. showed that methyl gentisate, an

alkyl ester of gentisic acid, derived from

Gentiana lutea roots was effective on

melanogenesis inhibition using mammalian

melanocyte cell cultures and cell-free extracts.

Moreover, the compound appeared to be non-

mutagenic as a topical skin-lightening agent [41].

Tumen et al. screened the dichloromethane,

acetone, ethyl acetate and methanol extracts of

the leaves along with the berries of Myrtus

communis, against tyrosinase. The

dichloromethane extract demonstrated the most

tyrosinase inhibition [42].

Hyun et al. reported that tyrosinase inhibition

activity of 70% methanol and pressurized liquid

extracts of Persicaria filiformis. was more than

90% [43].

In a study, Kilic et al. evaluated the antioxidant

and tyrosinase inhibitory activities of the

methanol extracts of immature and mature shell

skins of Pistacia vera. The results showed that

although the immature shell skin was rich in

phenolic and flavonoid compounds and also

demonstrated higher antioxidant activity in all

test systems compared to the mature one, the

tyrosinase inhibitory effect of the mature shell

skin was more potent [44].

Miyazawa et al. introduced one of the isolated

compounds from Polygonum hydropiper L.,

[(2R,3R)-(+)-taxifolin)], by a guided

fractionation method as a new tyrosinase

inhibitor alternative to cosmetic agents such as

arbutin and kojic acid [45]. In another research,

P. cuspidatum Siebold & Zucc. extract obtained

by supercritical fluid carbon dioxide extraction,

suppressed tyrosinase function and melanin

content via mushroom and B16-F10 cellular

based assay platforms which could be considered

as skin anti-tyrosinase agent [46]. In addition,

piceid (5,4′-dihydroxystilbene-3-O-β-D-

glucopyranoside), one of the stilbenes found in P.

cuspidatum root, has shown hypopigmentation

activity and tyrosinase inhibitory effect in

melanocytes, which were more considerable than

those of arbutin [47]. Leu et al. stated that

among the examined anthraquinones of P.

cuspidatum, physcion with great tyrosinase

inhibitory activity and impressive skin

permeability activity was the most potent

anthraquinone and could be a powerful candidate

for dermal use [48].

In a study, 67 tropical plants were evaluated for

their tyrosinase inhibition activity, and stated that

Portulaca pilosa demonstrated strong inhibition

of tyrosinase, which could be selected for

identifying new active phytochemical

constituents in the development of skin-

Ghafari S. et al.

78 RJP 4(4), 2017: 71-85

whitening agents [26].

Matsuda et al. showed that the ethanol extracts of

Prunus x yedoensis Matsum., P. zippeliana Miq.,

P. amygdalus Schltr., P. persica (L.) Batsch and

P. armeniaca L., have potential tyrosinase

inhibitory effect in vitro, while P. x yedoensis

and P. zippeliana leaves reduced the melanin

amount by auto-oxidation [49]. The clinical

efficacy evaluation of one herbal formulation for

facial blemishes containing P. amygdalus oil

showed that after applying it twice daily for 6

weeks, a significant decrease in blemishes

(p<0.05) was observed with no significant

adverse reactions [50].

The whole plant extracts including: ethyl acetate

and 50% propylene glycol of Raphanus sativus had over 50% tyrosinase inhibitory effect, while

ethyl acetate extract demonstrated more potent

ability [51].

Based on studies, Rheum palmatum L. and R.

officinale L. have demonstrated tyrosinase

inhibition properties (68% and 60%,

respectively) [52,53].

Silveira et al. agreed with the inclusion of R.

rhaponticum L. rhizome extract into cosmetic,

sunscreen and skin care products, for the

prevention or reduction of photo damages. This

was because R. rhaponticum rhizome extract

demonstrated inhibitory effect on tyrosinase via

mechanisms such as mushroom tyrosinase

method, tyrosine kinase activity in melanocytes,

as well as inhibition of IL-1α, TNF-α and α-MSH

production. In addition, in vitro antioxidant

properties of the plant extract against lipid

peroxidation and free radical scavenging has

been revealed [54]. In addition, a number of

isolated potent compounds such as 3,4',5-

trihydroxystilbene-4'-O-beta-D-(2"-O-galloyl)

glucopyranoside and 3,4',5-trihydroxystilbene-4'-

O-beta-D-(6"-O galloyl) glucopyranoside (from

R. officinale), rhapontine (from R. undulatum)

and its converted compound, rhapontigenin,

exhibited a competitive inhibition against

tyrosinase and also inhibited the biosynthesis of

melanin [53,55].

The results of melanogenesis evaluation by in

vitro and in vivo methods in foods revealed that

Rosa canina (dog rose) extract could potentially

be used as a natural inhibitor of polyphenol

oxidase and tyrosinase to preserve the quality of

fresh-cut vegetables and fruits [56]. In 2009, Fujii

and Saito reported quercetin isolated from the

ethyl acetate fraction of R. canina. It carries out

inhibition by two particular mechanisms

including tyrosinase inhibitory activity (reduced

31.6% melanin content) and protein expression

by in vitro method [57]. On the other hand, in

another study in 2011 by Fujii et al., it was

claimed that due to its very low content in R.

canina, quercetin would contribute only slightly

to the inhibition of melanogenesis and

procyanidin glycosides would be the main

compound which could reduce the production of

melanin [58].

In a research carried out by Muñoz et al., it was

suggested that the extraction method strongly

affected tyrosinase inhibition activity and the

cytotoxicity data. Among the different extracts

obtained from Ruta graveolens with water:EtOH

(1:1) using several methods, the one prepared by

percolation demonstrated the best mushroom

tyrosinase inhibition (44.99 ± 0.25%) and no

cytotoxicity effect was observed by in vitro

model (IC50< 1000 mg/ mL) [37].

Trigonella foenum-graecum L. was one of the

fifty-two Nepalese crude drugs traditionally used

for the treatment of hyperpigmentation, and was

screened for mushroom tyrosinase inhibitory

activity primarily. It showed 24.3% ± 8

tyrosinase inhibition with 91.4% inhibitory

activity of kojic acid [4].

In order to find a safe and permeable compound

for whitening against hyperpigmentation and

sunburn, Ookubo et al. performed intracellular

screening for melanogenesis inhibitors with 11-

arginine (11R), a cell membrane-permeable

peptide as a transdermal delivery system, fused

with several kinds of tyrosinase inhibitory

peptides from natural sources. According to the

study, one of the natural peptides found in gliadin

protein (a Triticum vulgare Vill. component)

Plants for treatment of hyperpigmentation in ITM

79

could exhibit potent inhibition on melanin

synthesis via melanin content measurement in

B16 4A5 melanoma cells with no cytotoxicity. In

addition, the whitening effect of the fused peptide

with pyrenbutyrate, a skin delivery enhancer, was

measured in a UV-induced sun-tanning guinea

pig model, and the results demonstrated a

significant inhibition of melanogenesis in

Masson-Fontana staining through histology study

[59].

Yao et al. investigated the tyrosinase inhibitory

effect of various legumes such as Vicia faba in

China, and claimed that its tyrosinase inhibition

activity significantly correlated with total

phenolic content and DPPH assays (p < 0.01)

[60].

Table 2 has shown a list of plants or their isolated

compounds with mushroom tyrosinase inhibition

activity (MTIA) based on modern researches.

Transcriptional regulation of melanogenic

enzymes

According to the study of Peng et al., the aerial

part of Achillea millefolium essential oil could

suppress melanin production, by the attenuation

of tyrosinase activity via the regulation of the c-

Jun N-terminal kinase (JNK) and extracellular

signal-regulated kinase (ERK) signaling

pathways. In addition, linalyl acetate was found

as the major functional component of the

essential oil [61].

The ethyl acetate extract of Citrus unshiu- press

cakes, by-products of the juice industry was

evaluated, for the anti-melanogenic potentials,

through the measurement of tyrosinase,

tyrosinase related protein (TRP-1, TRP-2) and

microphthalmia associated transcription factor

(MITF) in B16F10 cells, using Western blot

analysis. The results indicated that it inhibited

tyrosinase, TRP-2 and MITF expressions in a

dose dependent manner. Furthermore, HPLC

fingerpriningt of the extract revealed the presence

of rutin, arirutin, and hesperidin in different

quantities in the cakes [62].

It has been demonstrated that the methanol

extracts of Cucumis sativus leaves and stems had

the potential to inhibit melanin production in B16

cells at concentration of 100 µg/mL by reducing,

tyrosinase expression at the protein level. In

addition, among 8 compounds isolated from the

plant leaves, lutein was more potent in reducing

the expression levels of tyrosinase and wasfound

to suppress melanogenesis with IC50 value of

170.7 µM compared to the other compounds

[63].

It has been demonstrated that the ethanolic

extract of Lepidium apetalum seeds reduced UV-

induced skin pigmentation in brown guinea pigs

with no obvious side effects. In addition, it could

act as a hyperpigmentation inhibitor via a

mechanism involving IL-6-mediated down

regulation of MITF, a transcription factor

implicated in tyrosinase gene expression and

melanocyte differentiation, rather than a direct

inhibition of tyrosinase activity [64].

Wing-Ki Cheung et al. demonstrated the

inhibitory effect of 2,3,5,4′-tetrahydroxystilbene-

2-O-β-D-glucopyranoside, isolated from dried

tubers of Polygonum multiflorum, on tyrosinase

in cell-free kinetics. They demonstrated that the

anti-melanogenic activity of the compound was

mediated probably via a noncompetitive

inhibition on tyrosinase, down-regulation of the

expression of melanogenic proteins, and

reduction of tyrosinase/tyrosinase-related protein

1 (TRP-1) complex formation [65].

Inhibition of melanosome transfer

In a study, although combination of extracts of

Curcuma zedoaria and Aloe vera demonstrated

very low tyrosinase inhibition activity in extract

treated cells (50% to 90% for 1-5 µL extract

combination); it decreased melanogenesis

without altering the cell proliferation, and acted

as melanin transfer inhibitor to the keratinocytes

[66].

Skin hyperpigmentation is characterized by

increased production and accumulation of

melanin, which could be aesthetically

unfavorable, and develops serious skin diseases.

Nowadays, attention has been drawn to develop

cosmetic products with depigmenting effect [67].

Ghafari S. et al.

80 RJP 4(4), 2017: 71-85

Table 2. Plants or their isolated compounds with mushroom tyrosinase inhibition activity (MTIA) based on modern researches

Plant /Compound Plant

organ Extract

MTIA

Reference Inhibition %

IC50

Allium cepa

quercetin-3′-O-β-D-glucoside Ds * - 6.5 μM [25]

Althaea officinalis L Propylene glycol 50% 48 - [26]

Aristolochia bottae Ap Hexane - 117.8 µg/mL [27]

Aristolochia debilis

Magnoflorine St Methanol 36.5 (100μg/mL) - [28]

Astragalus sinicus S Acetone 93.8 (20 mg/mL) - [29]

Astragalus membranaceus

calycosin R Methanol - 38.4 µM [30]

Caesalpinia sappan

brazilein Hw Methanol -

21.21 mM

[31]

Carthamus tinctorius

N-feruloylserotonin S

Methanol 80%

(Ethyl acetate fraction) - 0.02 mM [32]

Carthamus tinctorius

N-(p-coumaroyl) serotonin S

Methanol 80%

(Ethyl acetate fraction) -

0.07 mM

[32]

Carthamus tinctorius

acacetin S

Methanol 80%

(Ethyl acetate fraction) -

0.78 mM

[32]

Citrus aurantifolia * * 69.4 (50 µg/mL) - [4]

Citrus aurantium * * 53.4 (50 µg/mL) - [4]

Citrus sinensis F Ethanol 50% 22.0 - [33]

Citrus grandis F Methanol 90.8 (10 mg/mL) - [34]

Fp * - 2.07 μg/mL [38]

Citrus sp.

Nobiletin Fp Methanol - 46.2 µM [36]

Citrus hystrix Fp Essential oil - 2.08 μg/mL [38]

Costus spicatus L Propylene glycol 50% 39 - [26]

Myrtus communis L, B ? 40.53 (200 μg/mL) - [42]

Persicaria filiformis St, L Methanol 70% 93.1 - [43]

Polygonum hydropiper

[(2R,3R)-(+)taxifolin)] Sp Methanol 70 (0.50mM) - [45]

Polygonum cuspidatum

Physcion * Ethanol ~70 (10 μM) - [48]

Portulaca pilosa L Propylene glycol 50% 93 - [26]

Prunus x yedoensis L Ethanol 50% 80.6 - [49]

Prunus zippeliana L Ethanol 50% 79.3 - [49]

Prunus amygdalus L Ethanol 50% 43 (500µg/mL) - [49]

Prunus persica L Ethanol 50% 42.6 (500µg/mL) - [49]

Prunus armeniaca L Ethanol 50% 42.1 (500µg/mL) - [49]

Raphanus sativus W Ethyl acetate 88.50 (5mg/well)

- [51] Propylene glycol 50% 68.73 (5mg/well)

Rheum palmatum Rh Methanol 68 (333µg/ml) - [52]

Rheum officinale Rh Methanol ~ 60 - [53]

Rheum rhaponticum Rh Methanol - 0.06 μg/ml [54]

Rosa canina M Distilled water 98.45 - [56]

Rosa canina

quercetine F * 68.4 - [57]

Ruta graveolens L Ethanol 50% 44.99 (2.5%W/V) [37]

Trigonella foenum- graecum S Methanol 24.3 - [4]

Vicia faba Lg Ethanol 70% 67.73 - [60]

* Not mentioned, -: Not done, ?: Not found, Ap: aerial part, B: berries, Ds: dried skin, Dt: dried tubers, F: fruit, Fp: fruit peels,

Hw: heart wood, J: juice, L: leaves, Lg: legumes:, M: mature fruit, R: root, Rh: rhizome, S: seed, Sp: sprout, St: stems, W: whole

plant

Plants for treatment of hyperpigmentation in ITM

81

Depigmentation can be achieved by regulating

the activity and transcription of tyrosinase,

tyrosinase related melanogenesis enzymes, the

uptake and distribution of melanosomes in

recipient keratinocytes, melanin and melanosome

degradation, and the turnover of pigmented

keratinocytes [2].Despite their benefits, a number

of current natural and synthetic ingredients

utilized in cosmetic products for the treatment of

hyperpigmentation would cause some harmful

and undesired side effects. Hence, there is need

to find new depigmenting agents with intense,

rapid and optional whitening effect, no harmful

side-effects which lead to elimination of

unfavorable pigments [2,68].

In this regard, there are several reviewed studies, regarding the natural depigmenting agents and the mechanisms of melanogenesis inhibitory effect of herbal medicine. In 2008, Lin et al. summarized natural skin whitening products involving tyrosinase blockers and the products blocking the upstream regulation points of melanogenesis [10]. In two separate studies, in 2009 Chang and Smith et al. surveyed and presented an overview of tyrosinase inhibitors from natural and synthetic sources [5,69]. In 2012, Loizzo et al. reviewed studies on tyrosinase inhibitors of natural and synthetic origins, and also provided the information for enhancing the quality of food in industries, utilizing potential tyrosinase inhibitors [70]. Furthermore, in 2015, Chen et al. introduced natural and synthetic melanogenic inhibitory agents [8]. As the use of plant extracts and herbs has its origins in ancient times [71], in the present study, topical used medicinal plants, for the treatment of hyperpigmentation were searched in Iranian traditional medicine (ITM) books. Based on the results, 71 traditional names with depigmenting effects were introduced in table 1. It should be noted that the scientific names represented 79 plant names, because some traditional names were matched with more than one scientific name based on the used botanical text references. Furthermore, among the plant families, Brassicaceae accounted for most plants found

followed by Fabaceae and Cucurbitaceae, respectively. In addition, 44% of the introduced plants have been mentioned in two ITM references as shown in table 1. Studying modern literatures revealed that about 40% of the traditional plants had been investigated for hyperpigmentation inhibitory effect with different mechanisms in order of priority such as controlling the tyrosinase activity, transcriptional regulation of melanogenic enzymes and inhibition melanosome transfer. In addition, Astragalus membranaceus, Citrus unshiu, Polygonum multiflorum and Rosa canina have exhibited more than one melanogenesis inhibitory pathway. Although many mechanistic points can be targeted, tyrosinase inhibition is still the most common approach in achieving skin whitening agents [5]. Using kinetic analyses, tyrosinase activity could not be easily examined. Furthermore, controversial results were obtained when purified mushroom tyrosinase or cell lysates of melanoma cells were used [2]. According to articles reviewed in our study, the applied concentration of plants for determining mushroom tyrosinase inhibition was mentioned in a few studies; therefore, it would be a bit difficult to compare the tyrosinase inhibitory effect of all plants in Table 2. On the other hand, among the studied plants with high repetition in ITM, Astragalus sinicus, Rosa canina and Vicia faba with high scores in ITM, exhibited over 50% inhibitory activity against tyrosinase compared to ascorbic acid as the positive control (68, 98.45 and 93.8%, respectively). In addition, some isolated compounds from Allium cepa, Astragalus membranaceus and Carthamus tinctorius have demonstrated tyrosinase inhibition activity. With regards to Table 2, the compounds isolated from some of the traditional used plants, including quercetin-3′-O-β-D-glucoside, magnoflorine, calycosin, nobiletin, brazilein, N-feruloylserotonin, N-(p-coumaroyl) serotonin, acacetin, [(2R,3R)-(+)taxifolin)], physcion and quercetine, have exhibited tyrosinase inhibitory effects similar to or more potent than the applied

Ghafari S. et al.

82 RJP 4(4), 2017: 71-85

positive controls in the studies. It is so important that in some cases, the mentioned compounds were introduced as depigmenting agents of cosmetic products. Some of the plants mentioned in table 2,

exhibited inhibitory effects lower than 50% on

mushroom tyrosinase that may act through

different melanogenesis inhibitory pathways,

which is not based on tyrosinase activity.

Conclusion

In the present review, among the 79 plants

introduced, over 50% are yet to be investigated

for depigmenting activity. Hence, these plants

would be good candidates for exploring new

herbal medicines, for skin hyperpigmentary

disorders.

Regardless of the fact that tyrosinase inhibitory

activity was the main applied method in this

review; several mechanisms could be involved in

investigating the whitening effect of these plants.

Due to the different modes of interference, it

seems that combined methods could be a better

approach for achieving new depigmenting agents.

Acknowledgments

This research was supported by a Grant (No. 159)

from Tradititional Medicine and Materia Medica

Research Center, Shahid Beheshti University of

Medical Sciences, Tehran, Iran. The authors wish

to thank the School of Traditional Medicine,

Shahid Beheshti University of Medical Sciences

for library support.

Declaration of interest

The authors declare that there is no conflict of

interest. The authors alone are responsible for the

content of the paper.

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